Oxazoiiones and rbrocess for



Patented Nov. 29, 1949 UN ITED STATES PATEN T 2-BENZYL-4-HYDROXYMETHWLENEJSI(4?) OXAZOLDN'ES .AND maooess r01:

MAKING SAME 14Claims. (Cl. 260 307) 1 "This invention relates to certain new chemical compounds and to improved processes ofpreparing them from readily available starting materials. More particularly, it relates to-certain new chemical compounds, 2-b-enzyl-4-hydroxymethylene-5'.(4') -oxazolone, and to the alkali metal, particularly the sodium saltthereof. These compounds, which may be prepared from. available starting materials,"have value in the synthesis of penicillin and compounds possessing penicillinlike activity. I

In preparing our new chemical compounds we maystart with the .methyl ester of ..oz-.-f01mla-phenacetamido acetic acid, sodium salt, prepared as described in the following-examples which are intended to be illustrative, but not -restrictive, 'of'our invention.

.EXAMPLEJ Methyl penaldate G (EHO CBH5CH2C.ONH CHCOOCHa Preparation of -a-formyl-a-phenacetamido.aceticacid methyl ester, sodium sa'Zt..A suspension 0?..25 mole of. freshly prepared sodium methoxide,

free 'from methyl alcohol, was :made in vca. 50.ml. dry benzene. To .this suspension was added a solutionof 13 grams ofmethyl formate (0.3.mole; 20% excess) .and about two-thirds ,of .52agrams (.25 mole) of phenacetamidoacetic-acid .methyl ester in.350 ml. dry benzene with thorough stir-- ring. The remainder of the ester wasaddedas a solid. Reaction began almost .=immediate1y; .a yellow .toorange coloration developed anda precipitatedoilbegan to appear within ten .toiiiteen minutes from .the beginning of tadditionlofathe ester. ,Stirring-was continued for six .hours, and

Dinitrophenylhydraeone of methyl menaldate G A solution of 2.5 N sodiummethoxide was prepared "by dissolving 5.75 g. sodiumlinme'thanol.

and diluting the product to .100 mLIin a volumetric flask. .iEight milliliters of this solution was evaporated to a sludge .under reduced ,pressure. Toluene (15 ml.) was added andthe suspension again evaporated to a solid. This solid was then 2,4dinitrophenylhydrazine.

was

2 covered with ether (about50 ml.) and 1. 5 g. 0.02 .mole) vmethyl .formate added. .Phenacetyl g'lyc'inemethylester (4.14 g.,.0.02 mole) was then added. T-The mixture .was shaken and a yellow viscous .o'il separated. lAfterstandingior.an hour or so,ithe oil becamemore viscous. Part of this Viscous material wasidissolved in water and .acidified with ahydrochloricacidsolution containing A ,-yellow 2,4-dinitrophenylhydrazone separated which melted C. when recrystallized fromr-ethanol. .After two more recrystallizations.frommethanol, the product melted at -181 (J. *lsoftens 1.779.) This product didlIlOE-adBPtGSS the melting point .of a 2,4-dinitrophenylhydrazone obtained from penicillin.

Partialanalysis igavewthe .iollowing 16.86. Found: C, 51.85; H, 3.98; N, $131.19; 16:65;

hydrous sodium sulifateianfltconcentrated. After final removal of .the solvent under vacuum pump, the residue (light 'brown oil) or crude formyl ester weighted 34.4 'gms.

This-oily ester 'was treated with 150 m1. of

dry"methanol in which approximately 5 g. of

dry hydrogen chloride gas had been "dissolved. After shaking for 'a time to putin solution, "it was-allowed -"to'-stand at room temperature for one hour. The methanol was then concentrated dow-n to about one-thirdbriginal volume, 100

mL -o'f'wchloroform added to the 'cooled residue and this solution shakenwith a half liter "of water, winch was extracted four more times with a little-chloroform. The combined chloroform extracts were shaken once 'more with Water, then with water containing enough sodium bicarbonate "-to remain basic (added as needed). The chloroform layer was dried over anhydrous sodium sulfate and concentrated. "The residue of crude acetalester-was 22.5 gramsaiterfinal drying under high vacuum to a viscous brown oil.

4 a-Rhenz Zacetamido-y8-,78-dimethomypropionic :acz'ii (penaldic G acid-.dimethylacetal) This material was treated with 88 ml. of normal sodium hydroxide (1 equivalent) and enough methanol added to put the oil into solution. This solution is allowed to stand at room temperature one and one-half hours; it is then concentrated down to about one-third its original volume, diluted with 250 ml. of water, and the solution extracted three times with 50-ml. portions of chloroform, which are discarded. The water layer is acidified slowly by addition of 50% sulfuric acid, keeping the solution cool, and simultaneously extracting the precipitated acid with chloroform until further addition of sulfuric acid produces no precipitate in the water layer.

The water layer is extracted four more times with 50-ml. portions of chloroform, and the chloroform layers combined, dried over anhydrous sodium sulfate and concentrated. The residual viscous oil, after final drying, weighed 12.5 grams. This crude acid is dissolved in a 1-1 mixture of ethyl acetate and petroleum ether with refluxing, and treated with 2 to 3 grams of Darco-G-GO activated carbon which removes some color. To the filtered liquor is added more petroleum other until incipient cloudiness at room temperature. On standing overnight in the icebox, 2.5 grams of acid melting at 109-111 C. (unc.) deposited.

Partial analysis gave the following:

Calcd. for C13H17O5N: C, 58.42; H, 6.42; N, 5.24. Found: C, 58.00, 58.11; H, 6.45, 6.26; N, 5.15.

EXAMPLE 5 Benzylamide o) a-phenylacetamido-;8,;3-dimethomypropiomc acid (penaldz'c G dimethylacetalbenzylamide) A mixture of one gram of fifi-dimethoxy-aphenylacetamidopropionic acid, methyl ester and one gram of benzylamine was heated at 120-130 C. for two hours. A small sample of the oily product in ether-petroleum ether deposited crystals when scratched. On cooling, scratching and seeding the reaction mixture in ether, a crystalline solid separated. When recrystallized from methanol, needles separated melting at 164- 165 0.

Partial analysis gave the following:

-Calcd. for C20H24N2O41 C, 67.39; H, 6.79; N, 7.86. Found: C, 67.53, 67.67; H, 6.48, 6.76; N, 8.07.

EXAMPLE 6,

fi-Methoxy-u-phenylacetamidoacrylic acid A solution of 1 g. [3,fi-dimethoxy, a-phenylacetamido propionic acid in 5 m1. acetic anhydride containing three drops of piperidine and 0.2 g. sodium acetate was heated on a steam bath for one-half hour. The cooled reaction mixture was extracted with petroleum ether. The petroleum ether was concentrated to an oil. A small portion of this oil was placed in a sublimer and heated under reduced pressure. The drop which collected on the condenser was scraped into a test tube and treated with onehalf milliliter of ether and scratched. Crystals separated. When recrystallized from ethyl acetate, a product was obtained melting at 199- 200 C. (uncorr.) Recrystallization did not raise the melting point. (193.5-194.5 corr.)

Partial analysis gave the following:

Calcd. for C12H13NO4I C, 61.28; H, 5.57; N, 5.96. Found: C, 61.31; H, 5.55; N, 6.24, 6.30.

EXAMPLE 7 2-benzyl-4-methomymethylene-5 (4) -oa:azolone Sixty-six grams of 1%,,8-dlmethoxyphenaceti 60 ml. of acetic anhydride and the mixture heated on the steam bath. The solid dissolved slowly until a clear light-colored solution was obtained. This solution was heated for ten minutes longer in order to complete the reaction. This additional heating has been found to be necessary, as working up without it gives only unreacted starting material. The reaction mixture was concentrated under reduced pressure in order to remove acetic acid and excess acetic anhydride and then washed with about 200 ml. petroleum ether, which caused the residue to solidify. The resulting solid was recrystallized from a small amount of ethyl acetate using just enough to bring it into solution and filter hot. The crystalline product is filtered ofi, washed with cold ethyl acetate, and dried immediately by pressing on a porous tile. This final drying prevents the darkening and gumming of the substance due to the presence of solvent and air. Yield, 33.3 gms. and 60% of theory; M. P. 92-93 C.

Partial analysis gave the following:

Calcd. for C12H11O3N: C, 66.35; H, 5.11; N, 6.45. Found: C, 66.00, 66.29; H, 4.89, 5.18; N, 6.62.

EXAMPLE 8 2-benzyl-4-hydroa:ymethylene 5 (4) oxazolone The solution made from 5.8 gms. of Z-benzyl- 4 methoxy methylene 5(4) oxazolone, 174 m1. of water, and 11.6 ml. of 2.5 N sodium hydroxide was shaken ice cold for 25-30 minutes. There was a small amount of solid material present which when isolated proved to be unreacted starting material, weight 0.5 gm.

A quantity of 11.6 ml. of 2.5 N hydrochloric acid was then added to the clear filtrate and the precipitate collected, washed with cold water and dried in a vacuum desiccator over phosphoric anhydride. Yield, 4.2 gms., based on ma.- terial used; M. P. 118-118.5 C. (dec.).

Although this material precipitated from aqueous solution, it is our experience that it can be recrystallized from water only with considerable loss. Material with this melting point, however, had satisfactory analyses for carbon, hydrogen and nitrogen. The melting point of the pure compound is actually higher than the above given figure, values as high as 124-125 C. having been obtained from certain purified samples.

Partial analysis gave the following:

Calcd. for C11H903N: C, 65.02; H, 4.47; N, 6.89. Found: C, 64.74; H, 4.34; N, 6.99.

EXAMPLE 9 2-benzyl-4-benzylaminomethylene- 5 (4) -o:caz0lone A solution of 50 mg. of 2-benzyl-4-methoxymethy1ene-oxazolone-4 in ether was treated with one equivalent of benzylamine in ether (total- Found; c, weed-vase; 74.18';.H,*5.77, 5.52.5140; N; 9;98.

' EXAMPLE 1*0 Penaldic amide-2,4-dini-trophenylhydrazone A suspension of 150 mg. of 2-benzyl-4- methoxy methylene 5(4) oxazolone in ml. concentrated aqueous ammonia was shaken mechanically overnight at room temperature. Nearly all of the oxazolone had dissolved and the deep 'yellow color which first'appeared had nearly all been discharged. The excess ammonia and water were removed under reduced pressureand dilute hydrochloric acid added until thesolution.

had a pH of 3. This treatment failed'to produce a crystalline product so the reaction mixture- 'was treated with an excess of 2,4-dinitropheny1- hydrazine and enough ethanol to give complete solution on warming. Onscratchingandcooling, a yellow flocculent precipitate settledout which melted at 218-2l9 C. after two recrystallizations from ethanol. This compound did not depress the melting point of a 2,4-dinitrophenylhydrazone obtained from penicillin after its inactivation with ammonia.

Partial analysis gave the following:

Calcd. for C1'7H16N606I C, 51.00; H, 4.03; N, 20.99. Found: C, 51.31; H, 4.28; N, 21.36.

The chemical reactions occurring may be represented as follows:

C H5CH CONHCH2COOMe +MeOOCH NaOCH;

0 CH2CaH5 NaOH 2,4-dinitro then acid phenylhydrazine C 0H5 C 112N112 Various changes and modifications may be 6 made in dur invention, as described hereim wftb out departing from the scope thereof.

We claim: I -'1.- A '2-benzyl 4-methyle'ne-5(4') -oxazolon'e a: the formula CCHzCt 5 wherein R is selectedfro'm the group consistifig er hydrogen, alkali metal, and lower-alkyl radicals.

-2. A -2 -"benZyl-4 alkoxyinethylene-5(4) oxazolone,-'said alkoxy radical being derived fi oma lower alkyl group.

3. Z-Benzyl --4 -hydroxyinetliylene 5(D enazolone.

4. Alkali metal salts of 2-benZyl 4-hydr6XY-' methylene-5 (4) -oxazolone.

5. The sodium salt of 2-benzyl'-4-hydr6ilymethylene-5 (4) -oxazolone.

'6. 2 Benzyl 4 methoiiymethylene'-"5(4)*- oxazolone. 7. In a process for preparing compounds- 1193?- ing the formula ROCH=C-C=O 1t wherein R is selected from the group consisting of hydrogen, alkali metal, and alkyl radicals, the steps that comprise reacting an alkyl ester of a-formyl-phenaceturic acid with anhydrous hydrogen chloride in a lower aliphatic alcohol to form the corresponding ester of a-phenylacetamido 5,,8 dialkoxypropionic acid, reacting the ester with alkali and acidifying the reaction mixture to form a-phenylacetamido-;9,B-dialkoxypropionic acid, and reacting the same with a mild condensing and dehydrating agent to form the corresponding 2 benzyl-4-alkoxymethy1ene-5- (4) -oxazolone.

8. The process of producing 2-benzyl-4-hydroxymethylene 5(4) oxazolone which comprises: reacting [3,5-diinethoxy-a-phenacetamidopropionic acid with acetic anhydride, concentrating under reduced pressure to remove acetic acid and excess acetic anhydride, washing with petroleum ether to cause the residue to solidify, recrystallizing and drying the resulting Z-benzyl- 4-methoXymethylene-5(4) -oxazolone, preparing a solution of the crystallized purified product in an aqueous alkaline solution, and precipitating the desired 2-benzyl-4-hydroxymethylene-5(4) oxazolone by the addition of an acid to said solution.

9. The process of preparing 2-benzyl-4-hydroxymethylene-5(4) -oxazolone which comprises reacting a-formyl-a-phenacetamido-acetic-acidmethyl ester with anhydrous methanol containing anhydrous hydrogen chloride to form methylor phenyl-acetamido-,8,B-dimethoXy-propionate, hydrolyzing said propionate, and heating the resulting a phenylacetamido-dfi-dimethoxy-propionic acid with acetic anhydride to form a 2- benzyl 4 methoxy-methylene-5(4) -oxazolone, and precipitating the desired 2-benzyl-4-hydroxy, methylene-5(4)-oxazolone by adding an acid to an alkaline solution of said 4-methoxymethylene compound.

10. The process that comprises reacting an a.- phenylacetamido-B,/3-dialkoxypropionic acid with a mild condensing and dehydrating agent to form the corresponding 2-benzyl-4-alkoxymethylene 5(4) -oxazolone. said alkoxy radical being derived from a lower alkyl group.

.11. The process that comprises reacting an acphenylacetamido-fi,p-dialkoxypropionic acid with a mild condensing and dehydrating agent to form the corresponding 2-benzyl-4-alkoxymethylene- 5(4) -oxazolone, and reacting the same with aqueous alkali to form an alkali metal salt of 2-benzyl- 4-hydroxymethylene-5(4) -oxazolone, said alkoxy radical being derived from a lower alkyl group.

12. The process that comprises reacting an aphenylacetamido-6,;8-dia1koxypropionic acid with a mild condensing and dehydrating agent to form the corresponding 2-benzyl-4-alkoxymethylene- 5(4) -oxazolone, and reacting the same with aqueous alkali and acidifying the reaction mixture to form 2-benzyl 4 hydroxymethylene-5(4) -oXazolone, said alkoxy radical being derived from a lower alkyl group.

13. The process that comprises reacting an 0:.- phenylacetamido-/3,B-dialkoxypropionic acid with acetic anhydride to form the corresponding 2- benzy1-4-alkoXymethy1ene-5 (4) -oxazo1one, said alkoxy radical being derived from a lower alkyl group.

14. The process that comprises reacting a phenylacetamido 5,5 dimethoxypropionic acid with acetic anhydride to form 2-benzy1-4-methoxymethylene-5 (4) -oxazolone.

STANTON A. HARRIS. GLEN E. ARTI-I.

CARL H. HOFFMAN. KARL FOLKERS.

REFERENCES CITED .The following references are of record in the file of this patent: 

